Prostaglandin E2 (PGE2) is a potent modulator involved in the pathogenesis of a variety of diseases such as inflammation, pain, arthritis, and cancer. PGE2 binds to at least four subtypes of PGE receptor, designated EP1, EP2, EP3, and EP4. Molecular pharmacology studies have revealed that all subtypes are 7-transmembrane spanning receptors that belong to the G-protein coupled receptor superfamily. EP1 activation stimulates the release of intracellular calcium; EP2 and EP4 stimulation both activate adenylate cyclase but differ in their response to certain ligands; and EP3 stimulation inhibits adenylate cyclase via inhibitory G-proteins (NPL 1).
Two distinct types of helper T (Th) cells, Th1 and Th2 cells, were discovered in 1986. Th1 cells are characterized by production of IFN-gamma and are thought to be crucial for the development of autoimmune diseases. On the other hand, Th2 cells are characterized by production of Interleukin (IL)-4 and are thought to play important roles in allergic diseases. Recently, a third subset of Th cell, called Th17 cells, was discovered and Th17 cells are characterized by production of a proinflammatory cytokine IL-17 (NPL 2). IL-17 has potent in inducing inflammatory cytokines such as TNF-alpha and IL-6 on various types of cells (NPL 3; NPL 4). It has been shown that IL-17-deficient mice are resistant to IBD and multiple sclerosis (MS) (NPL 5; NPL 6). Induction of IL-17 level in the serum and disease tissues has been detected in the patients with IBD, MS, psoriasis, and rheumatoid arthritis (NPL 7; NPL 8; NPL 9; NPL 10). These data suggest the involvement of Th17 cells in the development of various human autoimmune diseases and allergy.
Interleukin (IL)-23 is a heterodimeric molecule composed of p40 and p19 (NPL 11). Transgenic p19 overexpressing mice die before the age of 3 months following systemic inflammation, which indicates a prominent pro-inflammatory role for IL-23 (NPL 12). It has been demonstrated that IL-23 is important for expansion of Th17 cells in vitro (NPL 13). Mice lacking p19 were resistant to collagen-induced arthritis, experimental autoimmune encephalomyelitis and inflammatory bowel disease, because the generation of Th17 cells is impaired in the absence of IL-23 (NPL 14; NPL 15; NPL 16). In animal model and human, both IL-23 and IL-17 have been demonstrated to play important roles in many autoimmune diseases. For example, increases amounts of IL-23 have been associated with IBD, rheumatoid arthritis and psoriasis in human. And an anti-p40 antibody which neutralizes the effect of IL-23 demonstrates clinical efficacy in patients with IBD and psoriasis (NPL 17; NPL 18). These evidences suggest that IL-23 is important for the function of Th17 cells as well as the pathogenesis of autoimmune diseases.
AE3-208 is an EP4 antagonist which is generally used in non-clinical research experiments. AE3-208 was demonstrated to ameliorate MS and allergic contact dermatitis in animal models (NPL 19).
Autoimmune diseases develop when the patient's immune system is activated against substances and tissues normally present in the body. The pathogenesis of autoimmune diseases has yet to be clearly defined. Although the emergence of biological agents such as anti-TNF alpha antibody has greatly improved some kinds of autoimmune diseases, these agents are expensive and have risks of significant side effects. Therefore, a small-molecule medicine for autoimmune diseases is anticipated. Recent studies suggest that Th17, or both Th1 and Th17 mediate autoimmune diseases such as IBD, MS, RA, and psoriasis (NPL 20). Furthermore, PGE2-EP4 signaling has been demonstrated to promote immune diseases through Th1 and Th17 cells. EP4 antagonist (AE3-208) was demonstrated to restore immune systems and treat MS in mice (NPL 21).
The allergic disorder is a genetically and environmentally affected multifactorial disease. While the etiology of allergy has not been fully understood, IL-17 has been reported to play crucial roles in allergy. Induction of IL-17 was found in the sera of allergic asthma patients and of allergic contact dermatitis (NPL 22 and NPL 23). In addition, IL-17 deficient mice are resistant to cause allergic asthma and allergic contact dermatitis (NPL 24). Above evidences strongly suggest the close relationship of IL-17 as well as Th17 in the causative mechanism of allergy.
Moreover, the potential of EP4 antagonism in the therapy of some kinds of allergy was validated using AE3-208. AE3-208 showed potent inhibitory efficacy on the development (sensitization) in mice allergic contact dermatitis model (NPL 25). These data suggest that EP4 antagonism will be a potential mechanism for the prophylactic drug of allergy. However, AE3-208 failed to show the efficacy by therapeutic treatment in this study. In terms of the clinical value of the drugs in this area, drugs which are available in the therapeutic stage are highly valuable than drugs whose usage is limited in the prophylactic use. Even worse, AE3-208 aggravated rat in DSS (dextran sodium sulfate)-induced colitis model, an IBD model.
In addition, nonsteroidal anti-inflammatory drugs such as indomethacin, which may have similar immune mechanism to EP4 antagonist, also aggravated DSS-induced colitis (NPL 26), and make allergic contact dermatitis worse in contact hypersensitivity model (NPL 27).